Suggestions for subtyping based on psychiatric status in ME/CFS research

Background

In his recent comprehensive article on the need for subtypes, Jason outlines how the current heterogeneity in research samples may be holding back our knowledge of pathophysiology and optimal treatment for patients with ME/CFS (Jason et al, 2005). If one has research subjects who are heterogeneous, one will miss significant findings in subgroup eg. those with ongoing infectious symptoms or delayed gastric emptying because these distinct subjects will be diluted by the group as a whole some of whom may not have those particular aspects. In a field filled with differing opinions, the need for subtyping in research is an area of common agreement. One area in which it is generally agreed that subtyping is necessary is in the area of psychiatric symptoms and psychiatric diagnosis.

Part I. Psychiatric symptom questionnaires/rating scales

Psychiatric symptom rating scales such as the Beck and Hamilton depression inventories, the General Health Questionnaire and the SCL-90 are used to rate the presence and severity of psychological symptoms. Patients endorse an item such as "I feel sad" and then rate severity on a likert scale. In epidemiological studies of populations these scales are ideal for identifying symptom prevalence. In treatment they are ideal for monitoring progress in an individual. However in research with illness groups these rating scales can be misused and misinterpreted.

1. The questionnaires are normed on healthy people.

The problem with the instruments most commonly used is that they have been designed to detect psychological disorder in physically healthy people and the items have been designed and/or normed with physically healthy populations. As a result somatic items such as fatigue, nausea, sleep disorder, gastrointestinal symptoms or cognitive dysfunction are scored as an indication of psychological disorder. This has resulted in overdiagnosis of psychological disorders in patients with many chronic medical disorders such as Rheumatoid Arthritis (RA), CFS and FM when instruments such as the Minnesota Multiphasic Personality Inventory (MMPI), Beck Depression Inventory (BDI), General Health Questionnaire (GHQ) are used. Farmer et al have reported that the use of the BDQ (the most common self report depression inventory) and the GHQ (screen for psychological distress) are inappropriate in patients with CFS because the items which load for depression and psychological distress overlap with the diagnostic criteria for CFS.

The use of the MMPI in such populations is particularly problematic. Pincus et al reported that patients with RA have elevated scores on the hypochondriasis, depression and hysteria scales of the MMPI not because they are psychologically distressed but because their physical symptoms load to these scales (Pincus et al, 1986). Goldenburg adds that the use of the MMPI is inappropriate for any patients with chronic pain because of the high false positive rate (Goldenberg, 1989). This hypothesis has been proven in two studies that demonstrated normalization of abnormal MMPI scores after treatment of chronic pain (Sternbach & Timmermans, 1975;Mongini et al, 1994).

2. Patients with ME/CFS may have high levels of emotional distress

Many subjects with ME/CFS, especially those who do not have medical validation and appropriate treatment have a high level of emotional distress. On rating scales such as the SCL-90 such patients will score high on most of the sub-scales (McGregor et al, 1996). If one interprets these high scores as being evidence of psychiatric disorder one may misinterpret emotional concern secondary to chronic illness, social stigmatization and poor medical care as psychiatric disorder.

3. In ME/CFS there is iatrogenic emotional distress

Finally, the impact of the attitudes of health professionals, insurers and society towards people with serious, chronic disorders for which no objective evidence is available with current medical technology should not be underestimated (Twemlow et al, 1997). Many patients appear highly anxious, distrustful and defensive in an interview especially when they have not developed a therapeutic relationship with the interviewer and/or when they suspect the interviewer does not believe the validity of their complaints. This is especially likely when previous experiences with health professionals have been traumatic.

Anxiety and mistrust on the part of patients will affect the subjective impressions of interviewers and the scores on such instruments as the MMPI, BDI, GHQ and SCL-90. Therefore, the use of these instruments is only appropriate when they are hand scored, somatic items are accurately attributed and contextual issues are taken into account.

The Hospital Anxiety and Depression Scale is recommended

The Hospital Anxiety and Depression scale (HAD) is a suitable self report instrument to screen for depression or anxiety in patients with CFS or FM because it was designed and normed on medically ill patients (Morriss & Wearden, 1998). One still has to guard against interpretation of high emotional concern as evidence of psychiatric disorder.

Part II. Structured Diagnostic Instruments

Structured diagnostic instruments such as the Diagnostic Interview Schedule (DIS), CIDI (developed by the WHO) and the Structured Clinical Interview for DSM (SCID) are research tools used to establish in a standardized fashion whether an individual has a psychiatric diagnosis or not. Taylor et al have reported that the DIS, a structured interview overdiagnoses DSM IV psychiatric disorders in patients with CFS because of symptom overlap between the two constructs (Taylor, 1998).

These interviews all attempt to discern whether physical symptoms are of "medical" or "psychiatric" origin. When a physical symptom is endorsed the subject is asked "has your doctor told you that this symptom is explained by an existing medical condition?" If research subject were to answer "yes" to each of these prompts s/he would NOT be diagnosed with somatization disorder. However if the same subject, not having had his/her symptoms validated by his/her physician as being due to ME/CFS reported fatigue, pain, dizziness, difficulty swallowing, painful menstrual periods and increased heart rate, this patient would receive a diagnosis of somatization disorder by the computer. Johnson et al have shown that if somatic items on the DIS are scored as having a psychological origin the prevalence of somatization disorder in CFS is over 90% whereas if these items are attributed to the physical illness the prevalence of somatization disorder in CFS is 0% (Johnson et al, 1996). These studies suggest that attribution of somatic symptoms is the most important aspect of scoring screening instruments and that if a tester does not attribute the cause of symptoms correctly the test conclusions will be incorrect. When tests are scored by computer or using an inflexible algorithm correction of attribution is not possible.

The SCID is the Gold Standard

Because of these shortcoming, the Semi-structured Clinical Interview for DSM IV (SCID IV) is considered the gold standard for psychiatric diagnosis in medically ill patients (Taylor, 1998). This interview is laborious, requires a trained interviewer and is not feasible in clinical practice or in all but the best funded research.

Part III Clinical Diagnosis for Research Purposes

For many clinicians or researchers without the financial resources to purchase the SCID and hire a trained clinician to administer it, other methods of making accurate psychiatric diagnosis must be used. The following are adapted from DSM IV specifically for use with ME/CFS patients. The two most common, clinically significant psychiatric conditions comorbid with ME/CFS are major depression and generalized anxiety disorder. For each of these the following are described:

1.When to consider a psychiatric comorbid diagnosis in the presence of ME/CFS

2.A diagnostic algorithm

3.Instructions to apply that algorithm in ME/CFS populations

4.Further subtyping of clinical and research importance

DEPRESSION

Consider a diagnosis of comorbid depression when:

The depressive symptoms predated the physical disorder

Pessimism is generalized beyond health and illness related issues

The patient is stuck in depression and it is having a negative effect on treatment.

To Diagnose Major Depression in the presence of ME/CFS all four boxes must be checked

Does the subject currently have 5 or more of following symptoms?

depressed mood (sad or empty) most of the day nearly every day

decreased interest or pleasure in most activities nearly all the time

significant (>5% change) weight loss or weight gain not due to dieting and/or change in appetite (up or down)

insomnia or hypersomnia nearly every day

objective (notable by others) psychomotor agitation/retardation nearly all the time

fatigue or loss of energy nearly every day

feelings of worthlessness or excessive guilt nearly every day

decreased ability to think or concentrate or indecisiveness nearly every day

Duration of > 2 weeks

Level of functioning decreased from before

Must have either depressed mood or loss of interest or pleasure

The last point should prevent patients with physical symptoms only being classified as depressed. According to DSM IV if the subject has physical symptoms only ie. items 3,4,5,6,8 only the diagnosis of depression cannot be made. If the subject has symptoms 3,4,5,6,8 AND has items 1,2 or 7 then the criteria are met.

Four subtypes of depressive affective disorder commonly seen in ME/CFS

1. Reactive grief due to loss of health, social connections, family support, financial capability, career and uncertainty re all of these.

Ask the patient whether s/he would feel the same way if his/her health, finances and social problems improved. If the patient say "yes" the depression is primary not reactive.

2. Biological change in mood/cognition as part of the physical disorder of ME/CFS (similar to mood change in MS or Parkinson’s disease).

Ask the patient: "does it ever happen that you are having a good day with respect to energy but a bad day with respect to mood?" If the patient says "yes" then the mood disorder is independent of the ME/CFS.

3. Comorbid depressive disorder

same as #2

4. Mood change due to medication or food or withdrawal from either

This requires a careful drug and diet history. Ask the patient "Could you stop eating [favorite food]… ?" If the patient says "no", this food may be having mood stabilizing effects and/or addictive traits.

How to subtype

Teaching the patient careful self observation skills and using daily ratings of mood and other symptoms can help distinguish patients whose mood problems are biological and associated with ME/CFS and other types of mood changes. Biological mood changes vary in parallel with physical symptoms, other types of mood problems are more independent.

ANXIETY

Consider comorbid anxiety disorder when:

Anxiety predated the physical disorder

Anxiety is generalized and not limited to health and health care related issues

Patient is unable to cope with or resolve anxiety over the long term

Diagnosing Generalized Anxiety Disorder in the presence of ME/CFS (must tick all 6 boxes for diagnosis)

Does the subject have:

Excessive worry on most days (about many things, not just illness)

Duration >6 months

Difficulty controlling worry

Must have 3 or more of the following symptoms:

feeling restless or keyed up

easily fatigued

difficulty concentrating/mind going blank

irritability

muscle tension

sleep disturbance (difficulty falling asleep or unrefreshing sleep)

Symptoms cause clinically significant distress/impairment

Symptoms are NOT due to direct physiological effects of a medical condition (eg. ME/CFS)

Most subjects with ME/CFS will have 3 or more of the physical symptoms of GAD and many are worried about their health and related problems. However most will not be excessively worried about life every day and/or have difficulty controlling their worry. Therefore the necessary inclusion of items 1,3 and 6 differentiates ME/CFS patients from psychiatric cases.

Four types of anxiety are commonly seen in ME/CFS

1. Anxiety about health e.g. prognosis, cause of symptoms or unpredictability of symptoms

Ask the patient "if you knew your diagnosis and believed it and knew what would happen to your health in the future would this change your level of anxiety/fear?" If the patient say "yes", the anxiety if primarily about health.

2. Anxiety as a result of the impact of having ME/CFS e.g. loss of social connections, loss of family support, financial hardship, loss of career. Anxiety about being denied disability payments is common.

Ask the patient "if you had no financial problems and your friends and family understood and were supportive, would you still be anxious?" If the patient says "yes" then the anxiety if independent of the life situation.

3. Comorbid anxiety disorder; GAD and social anxiety being the most common

Same as #2

4. Biological anxiety as part of the physical disorder of ME/CFS

Ask the patient: "does it ever happen that you are having a good day with respect to energy but a bad day with respect to anxiety?" If the patient says "yes" then the anxiety disorder is independent of the ME/CFS.

Conclusions

Subtyping subjects with ME/CFS by level of emotional distress and psychiatric disorder is critical to accurate, useful research. Of the commonly used symptom rating scales, the Hospital Anxiety and Depression Scale is recommended because it was designed for use in medically ill individuals and will not overestimate the amount of emotional distress in ME/CFS populations. Of the commonly used psychiatric diagnostic rating scales, the SCID is recommended because it will not overestimate the prevalence of co-morbid psychiatric disorder if the interviewer is well trained in the assessment and attribution of overlapping symptoms. For clinical research where funds do not allow the use of the SCID, the above adaptation of the DSM is recommended to be applied by the clinician based on knowledge of psychiatric diagnosis and the patient being assessed.